Synthesis of pseudoionones



United States Patent 3.439.042 SYNTHESIS OF PSEUDOION ONES Emile H.Eschinasi, Montclair, and Mary Lou Cotter,

East Orange, NJ., assignors to The Givaudan Corporation, New York, N.Y.,a corporation of New Jersey No Drawing. Filed June 24, 1964, Ser. No.377,503 Int. Cl. C07c 33/02 US. Cl. 260594 9 Claims ABSTRACT OF THEDISCLOSURE R may be lower alkyl or lower alkylene having up to 6, Catoms, phenyl, benzyl or cycloaliphatic.

The present invention relates to a novel process for making6-substituted ionones and to certain novel substances made thereby.

An object of this invention is to provide a novel process for makingirones in a technically simple and commercial feasible manner.

Another object is to afford a synthesis for valuable perfume materialsfrom relatively inexpensive raw materials by a process which results inexcellent yield and which does not require a large number of steps.

Other objects will become apparent from the following detaileddescription.

Alpha-irone is a valuable perfume material, as are also the beta andgamma irones. They are found as the principal components in violetflowers.

Irones may be represented by the following structural formula, in whichthe encircled 3-carbon atom denotes the fact that double bonds aredistributed along the neighboring carbon atoms from the 3-position:

Thus, alpha-irone has the double bond in the 3-4 position, beta-ironehas the double bond in the 23 position; and gamma-irone has the doublebond in the 37 position. It is also known that the alphaand gamma-ironescan exist in cis-transforms.

Accordingly, it will be understood that wherever the context so permitsor requires the structural or other representation is intended toinclude all the forms of the 6- substituted ionones, as well as any andall stereoisomers thereof.

Numerous proposals have been made in the patent and scientificliterature regarding methods of producing irones. However, the lowyields and the large number of steps of prior processes leave much to bedesired.

We now have found a new approach to making irones from simple rawmaterials, in a few steps and in excellent yields. Our process alsoenables us to prepare other 6-substituted ionones. Indeed, it has beenfound that the 6-lower alkyl-substituted ionones having from 2 to 6carbon atoms possess unexpectedly desirable olfactory properties,including, for example, an odor persistency over 7 times that ofalpha-irone.

In a broad aspect, our invention comprises the discovery that Grignardreaction products containing alpha-hydrogens next to an alkoxy groupcould be subject to oxidation to carbonyl derivatives by treatment withan excess of carbonyl derivatives such as acetone, or other ketones, oraldehydes and subsequently reacted with the excess carbonyl reagent togive aldol condensation products. It will, therefore, be appreciatedthat our invention is not, in this broad aspect, merely limited to aprocess for making 6- substituted ionones.

Nevertheless, for purposes of illustration and in order to exemplify thepreferred way we now envisage for the carrying out of our invention, weshall describe its application in the process for making 6-substitutedionones, more especially, irones, and still more especially, alpharrone.

In the aforementioned broad aspect, and as applied to makingalpha-irone, our process, in essence, may be represented in thefollowing accepted abbreviated form:

This reaction sequence represents the fact, for example, that when6-ketodihydrogeraniol, which we obtained in good yield by thesaponification of the perchloric acid-treated epoxydihydrogeranylacetate, was treated with two moles of methyl magnesium halide and thentreated with acetone we obtained a hydrated pseudoirone (III) (R=CHwhich, upon treatment with mineral acid such as phosphoric acid, wasconverted to alpha-irone in good yields.

In addition to the 6, 9-dimethyl-9-R-9 hydroxy-undeca- 3-5-dien-2-one(III), a small amount of 3-7 dimethyl-6- R-2-octene-1-6-diol (IIIa) isalso obtained in accordance with the present process.

We now believe that the mechanism of the conversion of II to III asdepicted in the following reaction sequence involves hydrogen transferfrom the primary alkoxide H H COMgX I CH0 H ornoooH: S curls-43H,

R OMgX \OMEX /OMgX IIIb IIIc isopropanol alkoxide IIIb to acetone toform the intermediate aldehyde IIIc and isopropanol alkoxide. Thereactive intermediate aldehyde IIIc condenses with excess acetone toform 111 in a typical aldol condensation:

Ill:

III

As already indicated, our process is not limited to the preparation ofirones, nor, indeed, merely to the preparation of 6-alkyl ionones, but,instead, it can be applied to form other 6-substituted ionones,including those which are substituted in the keto-containing side chain,as well as reaction products formed by the aldol condensation of IIIcand ketones other than acetone, or aldehydes.

We shall now indicate some of the modifications of our process wepresently contemplate, as well as the reaction conditions which we havefound to yield satisfactory results.

In place of the epoxydihydrogeranyl acetate (I) we can employ thecorresponding acetate formed from neryl acetate or a mixture of neryland geranyl acetates.

Also, in place of the acetate (I), other esters, such as the formate,the propionate, the butyrate, the benzoate, etc., may be employed. Ingeneral, any carboxylic acid ester may be used. For economic reasons itis preferred to use the acetate.

In place of II we may use esters having the formula:

CHORr where R, is an acyl radical, preferably a lower acyl radicalhaving from one up to carbon atoms.

As suitable Grignard reagents, RMgX, many of which are now available incommercial quantities from Metal & Thermit Corporation, New York, we maymention (1) those in which R is an alkyl or alkylene radical having upto 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl, amyl, isoamyl, t-butyl, hexyl, allyl and vinyl; or (2) inwhich R is an aryl or aralkyl radical such as phenyl and benzyl; or (3)in which R is a cycloaliphatic radical such as cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl. X is a halogen, such as chlorine, bromine andiodine.

Specific examples of operable Grignards include methyl magnesiumchloride, methyl magnesium bromide, methyl magnesium isodide, ethylmagnesium chloride, ethyl magnesium bromide, ethyl magnesium iodide,propyl magnesium chloride, propyl magnesium bromide, propyl magnesiumiodide, butyl magnesium chloride, butyl magnesium bromide, butylmagnesium iodide, phenyl magnesium chloride, phenyl magnesium bromide,phenyl magnesium iodide, benzyl magnesium chloride, benzyl magnesiumbromide, benzyl magnesium iodide, cyclohexyl magnesium chloride,cyclohexyl magnesium bromide and cyclohexyl magnesium iodide.

In forming the aldehyde (IIIc) any carbonyl-containing compound may beused. Consequently, ketones and aldehydes in general may be employed.For purposes of 4 making ionones substituted in the keto-side chain werecommend that the applicable ketones should have a reactive methylenegroup, and should conform to the following formula:

where R and R are H or lower alkyl and alkylene groups, aryl, or aralkylgroups having up to 5 carbon atoms in the side chains. Examples of suchketones include methyl ethyl ketone, diethyl ketone, methyl propylketone, methyl isopropyl ketone, methyl butyl ketone, methyl isobutylketone, mesityl oxide, methyl t-butyl ketone, ethyl propyl ketone, ethylisopropyl ketone, and ethyl t-butyl ketone.

The epoxy geranyl acetate (I) or other esters may be formed from thecorresponding geranyl ester in the presence of organic peracids. Whileperphthalic acid is usually utilized in such a process we prefer to usethe cheaper and commercially available 40% peracetic acid in acetic acidsolution supplied by Becco Sales Corporation, Buffalo, NY. From one totwo moles of peracetic acid per mole of geranyl ester is used. We preferto use one mole since an excess of peracids tends to form the diepoxide.The temperature of the reaction could range from about 0-50 C. We preferto use about 1025 C. since at lower temperatures the reaction is veryslow and at a higher temperature the epoxy group is opened to form aglycol monoacetate. Around about 15-25 C. the reaction is fairly rapidand the epoxidation could be concluded within 1560 minutes of theintroduction of the peracetic acid. We also prefer to use sodium acetatefrom 1 to 5% by weight of the peracetic acid used in order to neutralizeany mineral acids, usually present in commercial peracetic acid.

The rearrangement of the epoxy to the keto group is made with strongmineral acids such as sulfuric or perchloric acid. We prefer to use thelatter because the yields are better and there is little by-productsformed (such as the opening of the epoxide cycle to form glycol or anallylic alcohol). The temperature of the rearrangement could be carriedout as high as 50 C. or as low as 0 C. We prefer to work between 10-35C. since these temperatures are conveniently close to room temperatureand the reaction proceeds at a good rate with the least amount ofby-products (10-15% A solvent is not necessary but could be used tocontrol the temperature of the reaction and reduce the amount ofby-products; ether, benzene, toluene and other water immiscible solventscould be used advantageously. We prefer to use benzene or toluene forthis reaction. The saponification of the intermediate keto ester to IIis made by conventional means using aqueous or alcoholic alkalies.

The Grignard reaction (II to III) is carried out by treating II with aGrignard reagent, RMgX, in 2 to 4 molar excess. We prefer to use from 2to 2.5 moles. Such Grignard reagents are now commercially available fromMetal & Thermit Corporation, New York, N.Y., in tetrahydrofuran (T.H.F.)solutions. The introduction of the ketoalcohol (II) to the Grignardreagent could be carried out in a variety of solvents such as ether,T.H.F., benzene, toluene, etc. We prefer to work in benzene or toluenesolutions. Commercial acetone (moisture below 0.15%) is used for thetreatment of the Grignard reaction product although other ketones andaldehydes could be used. In the latter case, of course, the reactionproduct would be different since the aldehyde IIIc will give differentcondensation products with the excess carbonyl derivative. Since thehydride transfer involving the alkoxide and the ketone is essentially anequilibrium type of reaction (analogous to the Meerwein- Pondorfreaction), we use from one to ten molar excess of the ketone. We preferto use three to five molar excess of the ketone, since below the lowerlimit little hydride transfer reaction takes place, whereas above thehigher limit, considerable self condensation of the ketone may takeplace with the formation of aldols and water, which deactivates thealkoxides and interferes with the hydride transfer. The temperature ofthe reaction may be carried out between -100 C. We prefer to use therange between 30-60 C. which is close to room temperature and theboiling point of acetone.

The isomerization or cyclization of the ketone condensation product(III) to a d-substituted ionone is carried out in known manner for thecondensation of pseudoionone to ionone.

In order to illustrate the invention, and not by way of limitation, wegive the following examples:

Example 1.-6,7-epoxydihydrogeranyl acetate 450 ml. of 40% peracetic acidsolution (Becco Chemicals) containing 17 g. anhydrous sodium acetate isslowly introduced into a mixture of 435 g. geranyl acetate and 450 ml.benzene containing 17 g. anhydrous sodium acetate. The addition is madewithin 30-45 minutes under ice water cooling and stirring, thetemperature remaining between 10-20 C. After the addition is complete,stirring is continued at room temperature for an additional 2-3 hours.The mixture is then washed twice with 1 volume of saturated sodiumchloride solution and then neutralized with 10% soda ash solution andthe solvent evaporated. Upon distillation the main part of the reactionproduct distills at 113 C. at 2 mm. pressure, n 1.4550-1.4555, yield420-440 g. Saponification value 262.5 (theory 264).

Example 2.6-ketodihydrogeranyl acetate To 150 g. 6,7-epoxydihydrogeranylacetate and 250 ml. dry benzene in a flask provided with good agitationand ice-water cooling, is added dropwise 1.8 g. HClO 70% within 10-15minutes and the temperature kept between 10-20 C. After stirring for anadditional 5 minutes the mixture is neutralized with 30% NaOH, thesolvent evaporated and the reaction product distilled. The main cut B.P.1091l0 at 2 mm. 7% 14570-14580 amounts to approximately 115 g. andcontains about 85% of the keto ester (by oxirnation).

Example 3.-6-ketodihydrogeraniol 315 g. fi-ketodihydrogeraniol acetate,120 g. KOH, 60 ml. water and 550 ml. ethanol are heated under reflux forone half hour, then 400 ml. aqueous ethanol is distilled oif. Thereaction mixture is then treated with two volumes of saturated sodiumchloride solution, extracted with benzene and distilled. The main cutdistills at 115- 118 C. at 1 mm. 12 1.47401.4750, carbonyl value 90% (byoximation), yield 225-240 g.

Example 4.6,7-ketodihydrogeraniol directly from geranyl acetate To 1108g. geranyl acetate, 1100 ml. benzene, and 42 g. sodium acetate is addedunder good agitation, within 2 hours, 1160 g. 40% peracetic acid (Becco)containing 42 g. anhydrous sodium acetate at a temperature ranging from25-30 C. After completion of the addition, stirring is continued for twomore hours at room temperature and the reaction mixture is then washedtwice with 2 volumes of sodium chloride saturated solution and finallyneutralized with Na CO The benzene is evaporated leaving about 1215 g.of a crude 6,7-epoxydihydrogeranyl acetate.

The crude epoxide is then slowly fed under good agitation into a flaskcontaining 1000 ml. dry benzene containing 3 g. 70% perchloric acidwhile the temperature is kept at 10-150 C. with an ice-water coolingbath. After the addition of about half the epoxide Within 25 minutes, anadditional 1 g. HClO was added, followed by another 2 g. HClO after thefeeding of three quarters of the epoxide. The whole addition of theepoxide took about 1 hour and was followed by the final addition of 2 g.HClO and the reaction was completed by stirring for 10 more minutes at10-15 C. (a total of 8 g. 70% perchloric acid was used).

The reaction flask was then fitted with a distilling head and 600 g. 50%aqueous sodium hydroxide was fed within 2-3 minutes under agitation. Thereaction mixture became viscous and warmed up while benzene distilledoff. After 15 minutes agitation, 100 ml. Water was added and the flaskheated to distill off the remaining solvent. An additional 100 ml. waterwas added to dissolve the crystalline salts and the reaction mixtureheated under reflux for an additional half hour. The top layer wasseparated, washed with NaCl saturated solution, slightly acidified withacetic acid and distilled. The main 6-ketodihydrogeraniol distilled atabout 115-120 C. at 1 mm. pressure n 1.4740-1.4750, yield: 470-520 g.,carbonyl value (by oximation), a higher boiling cut -B.P. 130-135 C. at1 mm. n 14840-14860 (75-90 g.) consisted of the3,7-dimethyl-2-7-dien-1-6-diol.

Example 5.6,9,lO-trimethyl-9-hydroxyundeca- 3-5-dien-2-one To a Grignardreagent prepared from 255 g. methyliodide (1.8 m.) in 300 ml. ether and45 g. magnesium (1.8 m.) in ml. ether, was added under ice-water coolingand stirring, 127.5 g. 6-ketodihydrogeraniol (0.75 m.) in 300 ml. drybenzene. After the addition was completed heating was started and thereaction temperature brought to about 60-70 C. by distilling off themajor part of the ether. The heating and stirring was continued for oneand a half hours more. The reaction mixture became viscous and wasfinally cooled to room temperature by means of an ice-water bath. 500ml. of dry acetone (moisture content 0.11%) was slowly added within15-20 minutes under strong agitation and cooling. The Grignard reactionproduct which dissolved as a clear amber solution was heated underagitation and refluxed. After about half an hour a rich precipitate ofbasic magnesium salt formed and after two hours reflux heating wasdiscontinued and the reaction mixture left overnight at roomtemperature. A solution of 130 m1. acetic acid and 260 ml. water wasthen added to dissolve the magnesium salts and the excess acetonedistilled until the pot temperature reached 100- C. 150 ml. water wasadded to the reaction mixture to dissolve the crystalline salts and thetop layer separated. After extraction with 100 ml. benzene, the toplayers were combined, washed with water and the solvent evaporated. Upondistillation some water of dehydration of the aldolization products wascollected followed by acetone condensation products (mesityl oxide,diacetone alcohol etc.) and a main cut (30%) consisting of 3,6,7-trimethyl-Z-octen-1-6-diol (1119.), RF. -130" C. at 1 mm. 111.4840-1.4850; followed by a major cut (40- 45%) of 6,9,10 trimethyl9hydroxy-undeca-3-5-dien-2- one. B. P. -145 C. at 1 mm. 11 1.5250,2,4-dinitrophenylhydrazone M. P. 177178 C.

Example 6.Alpha-irone 4 g. of6,9,10-trirnethy1-9-hydroxy-undeca-3-5-dien-2- one (III) was mixed with18 g. 85% H PO at 30 C. and the temperature maintained between 30-40 C.The reaction mixture was then decomposed with 100 ml.- water andextracted with 25 ml. benzene. After washing with a saturated NaClsolution, the benzene was evaporated and the alpha-irone mixturedistilled at 85-95 C. at 1 mm. yielding 3 g. 11 1.4980 possessing thecharacteristic violet odor of alpha-irone. The gas liquid chromatographyon a 20 M Carbowax column showed the product to consist of a mixture ofPercent Neo alpha-irone 18.5 Neo iso alpha-irone 71.5 Beta-irone 10 Themixture was almost identical with a product obtained, under the sameconditions, from an authentic sample of pseudo-irone. A4-phenylsemicarbazone M.P. 174 was isolated from the mixture which gaveno melting point 7 depression with an authentic sample prepared from neoiso alpha-irone. Example 7.-6,l-dimethyl-9-ethyl-9-hydroxyundeca-3,5-

diene-2-one To 1 mole of ethyl magnesium bromide prepared in theconventional way from 1 mole of ethylbromide (110 g.), 1 mole ofmagnesium (24.4 g.) in 250 ml. dry ether was added under ice watercooling 0.4 mole (68 g.) of 6-ketodihydrogeraniol in 200 m1. dry benzenewithin one half hour. The reaction mixture was then heated and the etherevaporated until the reaction temperature reached 60 C. and thenrefluxed for two and one half hours. After cooling at room temperature300 g. of dry acetone were slowly added under stirring and coolingwithin 20- 30 minutes and the reaction mixture which formed a clearsolution was refluxed for 4 hours under agitation, whereby a richprecipitate of magnesium salts formed. After cooling the reactionmixture was poured into a solution of 65 ml. acetic acid in 130 ml. ofwater containing 100 g. ice. The excess acetone was evaporated and theoily layer was separated. The mother liquors were extracted with 50 ml.benzene and the combined organic layers washed with saturated NaClsolution. Upon distillation there was collected about 40-45 g. of6,lO-dirnethyl-9-ethyl-9-hydroxy undeca-3,5-diene-2-one boiling at145-15S C. at 1 mm. n 1.5010. A small amount of approximately 2025 g. of3,7-dimethyl-6-ethyl-2-octen-l,6-diol boiling at 120- 125 C. at 1 mm. n1.47401.4755 was obtained as a light distillation cut.

Example 8.6-ethylionones g. of6,10-dimethyl-9-ethyl-9-hydroxyundeca-3-5-diene-2-one as obtained inExample 7 in 10 ml. benzene were mixed with 50 g. 85% phosphoric acidheated to 50 C. under agitation for 1-1.5 hours. The reaction mixturewas then quenched into 250 ml. water, the oil separated and the motherliquor extracted with ml. benzene. After washing the organic layer withsaturated NaCl solution the solvent was evaporated and the 6-ethyliononemixture was distilled at 120-125 C. at 1 mm. n 1.4950- 1.4985 (6-8 g.).It consisted of a mixture of four isomers in the approximate proportionsof 20:35:25 :15. Analysis calculated for C H O: C:8l.77; H=l0.97. Found:C=82.03; H=10.95. The odor was very flowery and pleasant with an irisnote which persisted over 2 weeks on the smelling paper whereas thealpha-irone sample lasted less than 48 hours.

As will now be understood by those skilled in the art, the processdescribed in the foregoing examples may be employed to form other6-substituted ionones, including those having substituents in the sidechain containing the carbonyl group. Thus, by stubstituting anequivalent amount of ethyl magnesium bromide for the methyl magnesiumiodide used in Example 5, 6-ethyl ionone can be obtained uponcyclization in accordance with Example 6. In similar manner, 6-propylionone, and 6-butyl ionone are obtained by substituting thecorresponding propyl magnesium iodide and butyl magnesium iodide,respectively, for the methyl magnesium iodide of Example 5. Side chainsubstituted 6-substituted ionones are obtained by substituting ketonessuch as methyl ethyl ketone, di-

ethyl ketone, methyl propyl ketone, methyl isopropyl ketone, methylbutyl ketone, methyl isobutyl ketone, mesityl oxide, methyl t-butylketone, ethyl propyl ketone, ethyl isopropyl ketone, ethyl t-butylketone for the acetone employed in Example 5.

The foregoing illustrates the practice of this invention which, however,is not to be limited thereby, but is to be construed as broadly aspermissible in view of the prior art and limited solely by the appendedclaims.

We claim:

1. A process, which comprises reacting, at a temperature within therange from about 0 C. to C. a compound having the following formula:

I CHzOH with at least twice the molar amount of a Grignard reagenthaving the formula:

where R is a member selected from the group consisting of lower alkylradicals and lower alkylene radicals having up to 6 carbon atoms,phenyl, benzyl and a cycloalkyl groups and X is a halogen and treatingthe resulting reaction product with at least twice the molar amount of aketone having the formula: RCH COCH R where R and R are selected fromthe group consisting 'of H, lower alkyl, lower alkylene, phenyl andaralkyl groups having up to 5 carbon atoms in the side chains.

*2. The process of claim 1, wherein RMgX is methyl magnesium halide, andthe ketone is acetone.

3. The process of claim 1, wherein R is methyl, X is iodine, and theketone is acetone.

4. The process of claim 1, wherein RMgX is ethyl magnesium halide, andthe ketone is acetone.

5. The process of claim 1, wherein R is ethyl, X is bromine, and theketone is acetone.

6. The process of claim 1, wherein RMgX is propyl magnesium halide, andthe ketone is acetone.

7. The process "of claim 1, wherein R is propyl, X is bromine, and theketone is acetone.

8. The process of claim 1, wherein RMgX is butyl magnesium halide, andthe ketone is acetone.

9. The process of claim 1, wherein R is butyl, X is bromine, and theketone is acetone.

References Cited UNITED STATES PATENTS 3,117,982 1/1964 Barton et al.260-587 LEON ZITVER, Primary Examiner.

M. M. JACOB, Assistant Examiner.

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,439,02 Dated April 15, 1969 Inventor(s) Emile H. Eschinasi et a1 It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below:

Column 1, line 20, column 3, line 53 and claim 1, lines 26 and 32"Alkylene" should read Alkenyl Column 2, line 53, "o,9diemthyl-" shouldread 6,10-dimethy1- Column 3, line :2, "CHOR should read Column 4, line6, "Alkylene" should read Alkenyl line 12; delete "mesityl oxide" Signedand sealed this 21st day of November 1972 (SEAL) Attest:

EDWARD M.FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissionerof Patents

